Project Summary: Increasing amount of evidence indicate that hypothalamic AgRP neurons control energy homeostasis by co-releasing NPY, AgRP and GABA to some specific post-synaptic targets in the brain. Recent studies suggested that activation of AgRP neurons promotes weight gain by simultaneously stimulating food intake and suppressing energy expenditure. However, it remains elusive as of how AgRP neurons organize a neural circuit to suppress thermogenesis and reduce energy expenditure in response to nutritional signals. The objective of this proposal is to gain mechanistic insights into the functional connectivity and key signaling components of a novel AgRP circuit that exerts distinct control of energy expenditure. Here, we obtained compelling results indicating that a subpopulation of AgRP neurons exert unique control of intrascapular brown adipose tissue (iBAT) thermogenesis by sending inhibitory projections to the ventral lateral part of the dorsal raphe nucleus (DRd) in the midbrain. Our central hypothesis is that a subpopulation of AgRP neurons, in response to peripheral nutritional signals, play a distinct role in suppression of energy expenditure by inhibiting MC4R- expressing 5-HT neurons in the DRd. We will test the hypothesis in the following aims: Aim 1: Determine whether a subset of AgRP neurons that project to the DRd plays a physiological role in control of energy expenditure; Aim 2: Determine whether AgRP signaling mediates thermogenesis and energy metabolism by suppression of MC4R signaling system in the DRd; Aim 3: Determine whether serotonergic signaling in the DRd plays a crucial role in the regulation of AgRP neuron- mediated energy expenditure. Our proposed studies will reveal mechanistic insights underlying the control of thermogenesis and energy metabolism by a novel neural circuit. Taken together, the potential outcome of proposed study would facilitate the elucidation of a more complete neural network and underlying signaling pathways in distinct control of energy expenditure, one of the key prerequisites to future development of effective treatment for obesity.